Progesterone is protective against insults relevant to the aging process and neurodegenerative disease. However, the impact of age,and whether mechanisms implicated in progesterone's protective effects translate to the ability of progesterone to preserve cognitive function is still unclear. In the first period of funding, we determined that progesterone is neuroprotective and that this protection was dependent on the ERK/MAPK pathway and neurotrophin signaling. In addition, our data suggested that the NMDA receptor may be a relevant downstream target of progesterone's protective effects. The NMDA receptor is an important mediator of hippocampal long term potentiation (LTP). Since the ERK pathway and neurotrophin signaling are also implicated in the regulation of cognitive function, we hypothesized that progesterone by itself protects against age-associated cognitive impairment by regulating the function and/or expression of NMDA receptors and associated hippocampal LTP. Further, we predict that the intactness of progesterone- induced signaling, NMDA receptor phosphorylation and/or expression, and LTP will predict successful cognitive aging in old mice. These hypotheses will be tested through the completion of the following 4 aims: 1) To determine if progesterone prevents against ovariectomy-induced cognitive deficits in young adult, middle aged and old C57BI/6 mice, and if such effects are associated with effects of progesterone on hippocampal LTP;2) To determine if progesterone regulates NMDA receptor expression and/or phosphorylation as a potential mechanism underyling its effects on LTP and cognition; 3) To determine if signaling mediators of progesterone-induced neuroprotection (such as ERK)mediate the effects of progesterone on NMDA receptor phosphorylation and hippcampal LTP;and 4) To determine if the intactness of progesterone-induced signaling, NMDA receptor phosphorylation (or expression) and regulation of LTP,predicts successful aging. The successful completion of this project will fill an important gap in our understanding of how progesterone alone regulates cognitive function, and will be achieved through extensive utilization of the the 3 Cores and substantial interaction with the other Projects. In addition to greatly expanding our understanding of progesterone neurobiology, the results may also impact how we consider hormones in treating such neurodegenerative diseases as Alzheimer's disease.